Dysfunktionale Lernvorgänge (wie z.B. Pawlowsche Konditionierung) können bei Patienten mit Alkoholabhängigkeit das Rückfallrisiko erhöhen, was innerhalb der vorliegenden Arbeit mittels drei Studien untersucht wurde.

Generalized anxiety disorder (GAD) is associated with painful physical symptoms (PPS). These post hoc analyses of previous trial data assessed PPS and their response to duloxetine treatment in GAD patients. Studies 1 and 2 (n = 840) were 9- to 10-week efficacy trials; study 3 (n = 887) was a relapse prevention trial comprising a 26-week open-label treatment phase and a 26-week double-blind, placebo-controlled treatment continuation phase. Mean baseline visual analog scale scores (VAS, 0–100; n = 1727) ranged from 26 to 37 for overall pain, headache, back pain, shoulder pain, interference with daily activities, and time in pain while awake. In studies 1 and 2, improvement on all VAS scores was greater in duloxetine-treated than in placebo-treated patients (p ≤ 0.01). In study 3, pain symptoms worsened in responders switched to placebo compared with those maintained on duloxetine (p ≤ 0.02). In conclusion, duloxetine was efficacious in the short- and long-term treatment of PPS, which are common in GAD patients.

Pour les patients diagnostiqués avec un cancer au stade précoce, les décisions de traitement dépendent de l’évaluation du risque de rechute métastatique. Les outils de pronostic actuels sont fondés sur des approches purement statistiques, sans intégrer les connaissances disponibles sur les processus biologiques à l’oeuvre. L’objectif de cette thèse est de développer des modèles prédictifs du processus métastatique en utilisant une approche de modélisation mécaniste et la modélisation à effets mixtes. Dans la première partie, nous étendons un modèle mathématique du processus métastatique pour décrire la croissance de la tumeur primaire et de la masse métastatique totale chez des souris traitées avec le sunitinib (un inhibiteur de tyrosine kinase ayant une action anti-angiogénique) administré comme traitement néoadjuvant (i.e. avant exérèse de la tumeur primaire). Le modèle est utilisé pour tester des hypothèses expliquant les effets différentiels du sunitinib sur la tumeur primaire et les métastases. Des algorithmes d’apprentissage statistique sont utilisés pour évaluer la valeur prédictive des biomarqueurs sur les paramètres du modèle.Dans la deuxième partie de cette thèse, nous développons un modèle mécaniste pour la prédiction du temps de rechute métastatique et le validons sur des données cliniques des patientes atteintes d’un cancer du sein localisé. Ce modèle offre des prédictions personnalisées des métastases invisibles au moment du diagnostic, ainsi que des simulations de la croissance métastatique future, et il pourrait être utilisé comme un outil de prédiction individuelle pour aider à la gestion des patientes atteintes de cancer du sein. / For patients diagnosed with early-stage cancer, treatment decisions depend on the evaluation of the risk of metastatic relapse. Current prognostic tools are based on purely statistical approaches that relate predictor variables to the outcome, without integrating any available knowledge of the underlying biological processes. The purpose of this thesis is to develop predictive models of the metastatic process using an established mechanistic modelling approach and the statistical mixed-effects modelling framework.In the first part, we extend the mathematical metastatic model to describe primary tumour and metastatic dynamics in response to neoadjuvant sunitinib in clinically relevant mouse models of spontaneous metastatic breast and kidney cancers. The calibrated model is then used to test possible hypothesis for the differential effects of sunitinib on primary tumour and metastases, and machine learning algorithms are applied to assess the predictive power of biomarkers on the model parameters.In the second part of this thesis, we develop a mechanistic model for the prediction of the time to metastatic relapse and validate it on a clinical dataset of breast cancer patients. This model offers personalised predictions of the invisible metastatic burden at the time of diagnosis, as well as forward simulations of metastatic growth, and it could be used as a personalised prediction tool to assist in the routine management of breast cancer patients.

The topic Needs of people addicted to drugs and alcohol to maintain succesful abstinence in aftercare was chosen. Aftercare is an important part of addiction treatment, but often overlooked and unused. The aim is to clarify the needs of abstinent persons addicted to alcohol and other non-alcohol drugs and their subsequent comparison. The thesis is divided into two parts, theoretical and practical. The theoretical part deals with the development of addiction, its diagnosis, description of drugs and treatments options. Chapters dealing with treatment are thoroughly discussed because of the individual usage during the treatment of addiction. Aftecare of addicted people and problems with relapse take place in this part of work. The second part deals with research focused on identifying the needs of addicted people to drugs and alcohol to maintain successful abstinence and their subsequent comparison. Clarifying of these needs can serve as a recommendation to other abstaining people or as a support to services in the system of aftercare to successful abstinence nowadays. KEYWORDS Addiction, addictive substances, drug addiction treatment, abstinence, relapse, aftercare for drug and alcohol rehab

Les cancers pédiatriques représentent la première cause de décès par maladie chez les enfants puisque 20% des patients présentent des résistances et rechutent. Les traitements actuels sont à leurs limites d'efficacité mais aussi de toxicité. L'amélioration des connaissances de la biologie des tumeurs résistantes et l'identification de nouvelles cibles moléculaires sont nécessaires pour ces pathologies rares, extrêmement diverses et mal comprises. Les oncogènes de fusion sont responsables de l’oncogenèse de ~ 20% des cancers. En raison de la biologie particulière des cancers pédiatriques, nous avons émis l'hypothèse qu’ils seraient dus à des oncogènes de fusion. Leur exploration, particulièrement à la rechute où les données actuelles sont limitées, permettrait de mieux comprendre ces pathologies et d’introduire de nouvelles cibles thérapeutiques. Notre premier objectif était de détecter de nouveaux transcrits de fusion parmi 48 patients pédiatriques en rechute inclus dans l'essai de médecine de précision MOSCATO-01 mené à Gustave Roussy. A partir de données de RNA-seq, nous avons détecté l’ensemble des fusions retrouvées dans ces tumeurs et classé les plus pertinentes selon leur fonction et leur potentiel thérapeutique. Un nouvel oncogène de fusion nommé LMO3-BORCS5 retrouvé chez un patient atteint de sarcome d'Ewing dans les biopsies tumorales à la rechute et au diagnostic, et dans diverses lignées cellulaires a particulièrement retenu notre attention. Nos études fonctionnelles montrent que LMO3-BORCS5 a un rôle important dans la tumorigenèse et la sensibilité au traitement et que BORCS5 fonctionnerait, in vivo, comme un gène suppresseur de tumeur. Ces résultats montrent le rôle critique des transcrits de fusion dans l'initiation et la progression tumorale ainsi que dans l’acquisition de résistance au traitement et que les fusions isolées ne doivent pas être ignorées. A l'avenir, la prise en charge des cancers réside en une médecine moléculaire de précision, les oncogènes de fusions représentant l'un des outils les plus remarquables en clinique. / Pediatric cancers represent the first cause of death by disease in children as 20% of patients harbor resistances and die from recurrence of the malignancy. Nowadays treatment are at their limits of efficacy but also toxicity. Improving the knowledge on the biology of the relapsed/resistant tumors and identifying new molecular targets are needed for these rare, extremely diverse and misunderstood pathologies. Fusion oncogenes are known to be major drivers of oncogenesis, responsible for ~20% of cancers. Due to their particular biology, we hypothesized that pediatric tumors would be more likely to harbor fusions and that their exploration, especially at relapse where very limited data are available, could help to understand the particularity of these malignancies and consequently to provide new therapeutic targets. Our first aim was to detect new fusion transcripts in a cohort of 48 pediatric patients at relapse included in the precision medicine trial MOSCATO-01, previously conducted in Gustave Roussy. From the RNA-seq data, we described the landscape of fusions in these tumors and classified the most confident candidates according to their biological function and druggability predictions. A new fusion named LMO3-BORCS5 found in biopsies of a patient with Ewing's sarcoma, at diagnosis and at relapse as well as in various cell lines particularly caught our attention. Functional studies showed that LMO3-BORCS5 has a high impact on tumorigenesis and treatment sensitivity and that BORCS5 would act, in vivo, as a tumor suppressor gene. Our results strengthened the critical role of fusion transcripts in tumor initiation, progression and resistance and reinforces the idea that a private fusion oncogene should not be ignored. Indeed, the future of cancer care lays in precision medicine, with fusion transcripts being one of the most remarkable tool for treatment decision.

No description available.

No description available.

Rituximab (R) is increasingly incorporated in reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic cell transplantation (alloHCT) in patients with B-cell malignancies, not only to improve disease control, but also to prevent graft-versus-host disease (GVHD). There are no randomized prospective data to validate this practice, although single center data and the CIBMTR analysis have shown promising results. We aimed at validation of these findings in a large registry study. We conducted a retrospective analysis using the EBMT registry of 3,803 adult patients with B-cell malignancies undergoing alloHCT (2001–2013) with either rituximab (R-RIC-9%) or nonrituximab (RIC-91%) reduced intensity regimens respectively. Median age and median follow up were 55 years (range 19.1–77.3) and 43.2 months (range 0.3–179.8), respectively. There was no difference in transplant outcomes (R-RIC vs RIC), including 1-year overall survival (69.9% vs 70.7%), 1-year disease-free survival (64.4% vs 62.2%), 1-year non-relapse mortality (21% vs 22%), and day-100 incidence of acute GVHD 2-4° (12% vs 12%). In summary, we found that addition of rituximab in RIC regimens for B-cell malignancies had no significant impact on major transplant outcome variables. Of note, data on chronic GVHD was not available, limiting the conclusions that can be drawn from the present study.

Fatigue is a prevalent and debilitating symptom that affects up to 97% of individuals with multiple sclerosis (MS). It can negatively influence the socioeconomic status, activities of daily living and quality of life for the affected individuals. Fatigue is multidimensional and abstract, thereby making it complex to understand, target and treat. Over the past 20 years, physical activity has become more recognized as a management method that could help with the alleviation of fatigue. One of the reasons could be due to the anti-inflammatory effects of exercise. However, due to the multi-factorial nature of fatigue and the heterogeneity of the training intervention protocols, the potential mechanisms that underlie the relationship between fatigue and exercise are still not fully understood. In 2013, Latimer-Cheung and colleagues developed an evidence based physical activity guideline (PAGs) for people with MS. Since then, studies have shown consistent beneficial effects of exercise on reducing fatigue in people with MS by adhering to the PAGs. To date, however, there are no published studies that examined the potential mechanism that underlie the beneficial effect of the PAGs on reducing fatigue. The primary purpose of this thesis was to evaluate the effects of adhering to the PAGs on fatigue in people with MS and to assess whether any exercise-induced changes in fatigue were associated with changes in inflammatory cytokines. The secondary purpose of this thesis was to evaluate the effects of exercise on depression, strength, aerobic fitness, muscular endurance and quality of life. This study had a wait-list control design. Participants with relapse remitting multiple sclerosis (RRMS) were recruited and randomized to begin with either a 12-week supervised exercise training program (G1) or a wait-list control period (G2). The training program involved at least 30 minutes aerobic training and resistance training for major muscle groups twice per week. The G2 group maintained their regular lifestyle. After 12 weeks, G1 reverted back to their usual lifestyle and G2 began their 12-week supervised exercise training. Following training, we found a reduction in fatigue and depression with increased strength and quality of life. No changes were observed in pro-inflammatory cytokines, aerobic fitness or muscular endurance. This is the first study that examined the underlying potential mechanism for the beneficial effects of exercise by adhering to the PAGs. Following the PAGs for 12 weeks results in significant improvements in fatigue, depression, strength and quality of life. However, our results do not support the role of inflammatory cytokines in mediating these improvements. / Thesis / Master of Science in Kinesiology

The susceptibility of adolescents to chemical addiction has become a major international concern. Approximately 25% of people in Central Asia and Eastern Europe who inject chemical substances are under the age of 20 years (Youth at the United Nations, 2006), while up to 75% of unintentional injuries among adolescents in America are related to substance abuse (Page & Page, 2003:196). On the national level, approximately 25% of adolescents under the age of 20 are involved in substance abuse (Western Cape Department of Social Services and Poverty Alleviation Transformation Plan, 2006:13). Focusing on the Western Cape, a report from the South African Epidemiology Network (2007:3) highlights that the youngest patient in in-patient treatment was nine years of age, and among 2 798 persons who received in-patient treatment, 27% were under the age of 20, more than any other age group in treatment. Treatment of adolescent chemical addiction should include preparation for treatment, treatment, and also aftercare services to ensure that the addicted adolescent develops skills to maintain sobriety (Meyer, 2005:292-293). Section Six of the South African Prevention and Treatment of Drug Dependency Act (1992) prescribes that chemically addicted persons should have access to professional aftercare services to ensure that treatment is not terminated prematurely. The motivation for this study was based on the fact that, despite this statutory requirement, the Western Cape Drug Forum (2005:3) identified the need for the development of aftercare services in 2005, indicating the lack of focus on aftercare as part of treatment. This concern was confirmed by practitioners in the field of adolescent chemical addiction and findings resulted from previous research regarding relapse experiences of chemically addicted adolescents (Van der Westhuizen, 2007:129-130). / Social Work / D. Phil. (Social Work)